PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is the leading cause of mortality in people with HIV (PWH) in sub-Saharan Africa, due in part to delays in diagnosis and timely treatment. While HIV-infected persons often first seek care at peripheral clinics, TB diagnostic testing equipment located in centralized laboratories require time-consuming specimen transport and processing, resulting in delayed diagnosis and patient drop-out from care. Use of a point-of-care urine-based test detecting mycobacterial lipoarabinomannan (LAM) has been successful in reducing mortality in a hospital setting, but the existing test is insensitive in ambulatory patients. The largest burden of undiagnosed TB is in PWH in non-hospital settings, and clinic-based testing assays and improved algorithms are urgently needed. A promising novel, rapid, urine-based tests (nuLAM) has been developed that may overcome many barriers to TB diagnosis, but has not yet been tested in a clinical setting. My central hypothesis is that rational use of next- generation POC LAM testing will be an effective intervention for PWH in South Africa. I will test this hypothesis with the following specific aims: 1) To develop an optimized clinical algorithm to identify HIV-infected outpatients for TB testing using POC uLAM and guide evaluation of nuLAM. 2) To determine the diagnostic accuracy of the next-generation LAM tests to detect TB in a population of HIV-infected outpatients attending a rural clinic in South Africa, compared to rigorous validation standards of TB culture and GeneXpert. 3) To estimate the population-level impact of nuLAM testing of outpatient PWH through costing and decision analysis. My career goal is to become a physician-scientist with a focus on developing and implementing diagnostic approaches to ultimately reduce morbidity and mortality from HIV-associated TB. I will use the opportunity of the K23 award to obtain mentorship in predictive modeling, implementation science, and diagnostics science. These skills are highly complementary to my strong background in epidemiologic methods and clinical research, and will enable me to translate epidemiologic research findings into tools to help clinicians and policymakers improve approaches to TB diagnosis. At the completion of the research and mentoring outlined, I will be well-positioned to launch an independent research career with the ultimate goal of improving diagnosis, treatment, and care of HIV-associated TB in sub-Saharan Africa.